Preparation of solutions of derivatives of dioxydiaminoarsenobenzene



Patented June 8, 1926.

' UNITED STATES PATENT/OFFICE;

sTuAR'r n. MAcnwEN, or TORONTQONTARIO, earmna PREPARATION OF SOLUTIONS or DERIVATIVES or nIoxYnIAMmoansnivoiannznnn No Drawing. Original application filed'lvllay 31, 1928, Serial No. 642,704. Divided and this application filed December 7, 1923. Serial 110,679,251.

This application is a division of my prior application No. 64.2,704, filed May 31st, 1923.

This invention relates to the preparation of solutions of the arsenical drugs commonly known as arsphenamine, neoarsphenamine, sulpharsphenamine and the like, and which are derivatives of dioxydiaminoarsenobenzene, and particularly to solutions of sodium dioxydiaminoarsenobenzene-methanalsulphoxylate, disodiumdioxydiaminoarsenobenzene and the sulpharsphenamine above referred to and which is described in the Public Health Reports of the United States Government pp. 27832798 vol. 37, No. 45. These substances are at present usually sold in powder form and the solutions for injection are made at the time of use, since solutions as now made rapidly become toxic. As solutions must be made with great care, it is desirable that they be made only by thoroughly competent persons, and it is also desirable to save the administrator the time and trouble involved in the making of the solutions. My object therefore is to devise a method of making solutions ready for use which will keep for long periods of time without developing toxicity. I am aware that it has been proposed to employ an inorganic reducing agent such as sodium hy-dro-sulphite to give increased stability to solutions of arsenical drugs, and also that sugar has been employed for that purpose, but it has not so far been proposed to employ both in the same solution. My invention therefore lies in the discovery that by the use of both the reducing agent and the sugar a solution may be produced which will keep for periods many times longer than a solution prepared with either alone, and that the keeping effeet is many times greater than the sum of the individual effects of the two reagents.

I attain my object by adding to the solution of the drug in water, one or more of the group termed in chemistry sugars, and a reducing agent such as an acid sulphite or hydrosulphite or sulphurous acid free or combined with abase, or the unsaturated thio acids, free or combined with a base.

Experiments so far show that substantially pure dextrose and sodium acid-sulphite (NaI-ISO give very satisfactory results, The amount of both the sugar and sodium acid-sulphite may vary considerably.

In practice I havefound that',-assuming solution containing 5 grammes of sodiumdioxydiaminoarsenobenzene methanal-sulphoxylate to be required, it may be prepared by dissolving it with 20 grammes of dextrose and 5 grammes of sodium acid-sulphite in 100 c. c. of water. I have also used larger proportions ofboth the sugar and of the sulphite, If'a stronger solution of the drug be required, a larger quantity both of the sugar and sulphite may be used. Care must be taken, however, not to use so much sugar that the solution becomes too viscous, or so much of the'sulphite as to have an irritating effect on the patient.

WVhile either the sugar or the sulphite alone have a marked effect in preventing the solution becoming toxic by keeping, I find that when used together there is an increased effeet several times greater than their indi vidual effects.

Another unexpected result of this invention is that the toxicity of the freshly made solution is materially reduced, being very much less than the toxicity of a solution prepared from the powder form of the drug in the ordinary manner, and this reduced toxicity is maintained as long as the solution has therapeutic value.

Other sulphites which I have found to work more or less satisfactorily are potassium acid sulphite and ammonium acid sulphite and pottassium and sodium meta bi sulphites.

The solution after preparation is put up in sealed ampules for distribution, and will be found to keep satisfactorily for long periods.

In preparing sulph-arsphenamine I have obtained a solution well adapted for sub cutaneous injection by using the following proportions.

5 grammes sulph-arsphenamine.

gramme sod. hydro-sulphite.

12 grammes dextrose.

20 c, 0. water.

3 c. c. 1 normal caustic soda solution.

The alkali is used to-overcome the tendeney oi solutions of sulph-arsphenamine to gel, sufficient being used to bring the solution to a condition in which it is only slightly acid.

In preparing the solution the sod. hydrosulphite is preferably added last as in this case the acidity of the sod; hydro-sulphite need not be: taken into account in calculating the quantity of alkali required.

What I claim is 1. A stable non-jellying solution of 'sulph arsphenainine containing a sugar, a soluble inorganic preservative, and an alkaline reagent. A r 2.' A stable non-jellying solutionof sulpharsphenainine containing a sugar, a soluble 1 preservative, and an alkaline re-agent.

3. A stable non-jellying' solution of sulpln arsphenamine containing a sugar, a soluble reducing agent, and an alkaline re-agent' 4. A stable non-jellying solution of sulpharsphenarnine containing a sugar, a soluble inorganic reducing agent, and an alkaline re-agent. g

V Signed at Bufialo,N. Y., this 30th clay of November 1923;

STUART R. MAoElVEN. 

